Developing gene and cell therapies for rare diseases: an opportunity for synergy between academia and industry

F Mavilio; Gene Therapy , (25 May 2017) doi:10.1038/gt.2017.36

For the last 20 years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market. Cooperation between academia and industry is an opportunity to de-risk innovative approaches and ensure a faster and more economical development of therapies for diseases with high unmet medical needs and low-profit expectations.

Blood–brain barrier peptide shuttles

Macarena Sánchez-Navarro, Ernest Giralt, Meritxell Teixidó, Current Opinion in Chemical Biology, Volume 38, June 2017, Pages 134-140, ISSN 1367-5931, doi:10.1016/j.cbpa.2017.04.019.

Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics.

Peptides shuttles present several advantages over the brain delivery system alternatives. For instance, peptides are amenable for chemical synthesis, and present low toxicity. Some of the challenges of its application are already being solved. The recent development of new and more efficient BBB-shuttles will lead to more pre- clinical studies, and hopefully, to clinical evaluations in the following years.

Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study

Harding, I. H., Corben, L. A., Delatycki, M. B., Stagnitti, M. R., Storey, E., Egan, G. F. and Georgiou-Karistianis, N. (2017), Mov. Disord.. doi: 10.1002/mds.27023

Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia.

Contemporary theories, models, and evidence of neural compensation and neural reserve firmly support the notion that neurofunctional changes underlying degenerative diseases are not only detrimental but also may be compensatory. This idea has driven a groundswell of research into novel therapeutic approaches designed to stimulate or maintain these compensatory cerebral processes through, for example, noninvasive brain stimulation, or cognitive therapies. Given the evidence that cerebral compensation may also operate in FRDA, these novel means of intervention represent exciting pathways for future research.

The present study motivates a reconceptualization of cerebral contributions to FRDA. In particular, cerebral alterations are likely not just secondary repercussions of cerebellar and spinal insults. Rather, cerebral changes may represent capacity limited compensatory processes operating at the network level of brain function, which serve to mitigate the behavioral impacts of progressive pathology. Critically, these novel findings inform development of new avenues of clinical intervention for FRDA.

In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles

Lucia Montenegro, Maria N. Modica, Loredana Salerno, Anna Maria Panico, Lucia Crascì, Giovanni Puglisi and Giuseppe Romeo; Molecules 2017, 22(6), 887; doi:10.3390/molecules22060887

Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters’ water solubility while increasing and prolonging their antioxidant activity.
In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.

Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI

Thiago Junqueira R. Rezende, Alberto Rolim M. Martinez, Ingrid Faber, Karen Girotto, José Luiz Pedroso, Orlando G. Barsottini, Iscia Lopes-Cendes, Fernando Cendes, Andreia V. Faria and Marcondes C. França; Hum Brain Mapp. 2017 May 23. doi: 10.1002/hbm.23655. [Epub ahead of print]

The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.

Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P < 0.001).

Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich’s ataxia cardiomyopathy

Stram AR, Wagner GR, Fogler BD, Pride PM, Hirschey MD, Payne RM (2017). PLoS ONE 12(5): e0178354. doi:10.1371/journal.pone.0178354

Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.
These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.

Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015

GBD 2015 Healthcare Access and Quality Collaborators (Ryan M Barber, Nancy Fullman, Reed J D Sorensen, Thomas Bollyky, Martin McKee, Ellen Nolte, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Cristiana Abbafati, Kaja M Abbas et al); The Lancet, Volume null, Issue null, DOI:10.1016/S0140-6736(17)30818-8

Funding: Bill & Melinda Gates Foundation.

Unfortunately those affected by a rare disease need a good response from the health system throughout all life, perhaps more than those who are affected by common diseases. Although it is a paper about public health in general it could give us an idea about what we can expect from our national health systems in 195 different countries.

National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.

Regulators of frataxin PATENT WO 2017037567 A1

Pfizer Inc., 9 Mar 2017. This invention relates to a method of treating a condition or a disease associated with decreased levels or activity of frataxin, including Friedreich's ataxia, comprising administering to a subject in needthereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof. Related methods, pharmaceutical uses and pharmaceutical compositions are disclosed herein.

Related press releases:
Recent Publication and Patent Application Referencing Apabetalone Support its Continued Development and Success,
CALGARY, May 23, 2017 /CNW/ - Resverlogix Corp. ("Resverlogix" or the "Company") (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).
Findings on Frataxin Expression and Friedreich's Ataxia:
Recently, Pfizer applied for a patent titled: "Regulators of Frataxin" (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich' ataxia (FA). RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich's ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.

Nrf2, cellular redox regulation, and neurologic implications

Eduardo E. Benarroch, MD; Neurology May 16, 2017, 88:20 1942-1950; published ahead of print April 19, 2017, 1526-632X  doi: 10.​1212/​WNL.​0000000000003946

Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.

Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration

Wilkins HM, Weidling IW, Ji Y and Swerdlow RH (2017). Front. Immunol. 8:508. doi: 10.3389/fimmu.2017.00508


Friedreich’s ataxia is caused by autosomal recessive inheritance of a mutant Frataxin gene. The product of the Frataxin gene is responsible for iron homeostasis within mitochondria, and loss of this gene in Schwann cells leads to reduced mitochondrial respiration, inflammation, increased mitochondrial iron concentrations, and cell death. COX2 expression is elevated in both animal models and Friedreich’s ataxia patient lymphocytes, an indicator of increased inflammation.

Nonpublication of Trial Results for New Neurological Drugs: A Systematic Review

Hakala, A. K., Fergusson, D. and Kimmelman, J., Ann Neurol.. Accepted Author Manuscript. doi:10.1002/ana.24952

Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively. Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.

Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis

Cai K, Tonelli M, Frederick RO, Markley JL. Biochemistry. 2017;56(3):487-499. doi:10.1021/acs.biochem.6b00447.

Physical Therapy for Cerebellar Ataxia

Akiyoshi Matsugi (2017). Physical Therapy for Cerebellar Ataxia, Neurological Physical Therapy, Prof. Toshiaki Suzuki (Ed.), InTech, ISBN 978-953-51-3114-4, Print ISBN 978-953-51-3113-7, Published: May 10, 2017 under CC BY 3.0 license.

Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.

Inducible And Reversible Phenotypes In A Novel Mouse Model Of Friedreich's Ataxia

Vijayendran Chandran, Kun Gao, Vivek Swarup, Revital Versano, Hongmei Dong, Maria C. Jordan, Daniel H. Geschwind; bioRxiv 137265 This article is a preprint and has not been peer-reviewed doi:10.1101/137265

We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. The reversibility of knockdown also allowed us to determine to what extent observed phenotypes represent neurodegenerative cell death, or reversible cellular dysfunction.

Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed.

Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo

James L. Miller, Myriam Rai, Normand L. Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R. Spencer; Neuropharmacology, Available online 11 May 2017, ISSN 0028-3908, doi:10.1016/j.neuropharm.2017.05.011.

STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo. RhEPO, STS-E412 and STS-E424 increase FXN by up to 2-fold in primary human neuronal cells and in retinoic-acid differentiated murine P19 cells. In primary human cortical cells, the increase in FXN protein was accompanied by an increase in FXN mRNA, detectable within 4 h. RhEPO and low nanomolar concentrations of STS-E412 and STS-E424 also increase FXN in normal and FRDA patient-derived PBMC by 20%–40% within 24 h, an effect that was comparable to that by HDAC inhibitor 4b. Unexpectedly, rhEPO-treated KIKO mice developed severe splenomegaly, while no splenomegaly was observed in STS-E412- or STS-E424-treated mice. RhEPO, STS-E412 and STS-E424 upregulate FXN expression in vitro at equal efficacy, however, the effects of the small molecules on FXN expression in the CNS are superior to rhEPO in vivo.

STS-E412 (2-[2-(4-chlorophenoxy)ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine),nonpeptidyl compound selective activator of the tissue-protective EPOR/CD131 receptor.

Building the patient community

F Raffai and O Timmis; Gene Therapy (3 May 2017) doi:10.1038/gt.2017.

There are many challenges in conducting rare disease research. The conditions are often poorly understood, small patient populations are dispersed around the world, and there are limited funding opportunities. Patient groups can serve as a key partner in overcoming these challenges, as they understand the impact of rare conditions on patients’ lives. This gives patient groups valuable scientific insights into the disease. This can be used to create research strategies, address research bottlenecks and directly fund research that appropriately addresses patient needs. Patient groups can also play a critical role in recruiting and retaining patients for clinical trials, which reduces time and resource waste. By partnering with patient groups, research teams can improve efficiency of research and best meet the needs of patients. Researchers can also play an important role in building and supporting patient groups to unlock these benefits.

Improve Compassionate Use Programmes to ensure patients’ early access to medicines

EURORDIS-Rare Diseases Europe has published a new position on compassionate use, calling for the adoption of measures to revolutionise patients’ access to new medicines through Compassionate Use Programmes (CUP).

The length of time needed to develop a medicine varies, but on average it takes five to seven years, usually followed by the regulatory process and its legal timeframe, followed finally by pricing and reimbursement negotiations. Not all patients have the time to contemplate this relatively long process: their disease worsens, they gradually lose their body functions, and eventually die. In addition, at the same time as this inescapable deterioration is taking place, they can hear about “promising results” coming in the news, in real time. No other situation can be a source of greater despair in a patient’s life: dying and yet being aware a possible medicine is approaching the market.

Mechanisms of iron- and copper-frataxin interactions

Thi Hong Lien Han, Jean-Michel Camadro, Renata Santos, Emmanuel Lesuisse, Jean Michel El Hage Chahine and Nguyêt Thanh Ha-Duong; Metallomics, 2017, Accepted Manuscript. DOI:10.1039/C7MT00031F

Frataxin deficient Δyfh1 yeast cells exhibited a marked growth defect in the presence of exogenous Cu or Mn. Mitochondria from Δyfh1 strains accumulated also higher amounts of copper, suggesting a functional role of frataxin in vivo in copper homeostasis.

Peripheral nerve ultrasound in friedreich’s ataxia

Eoin Mulroy, Luciana Pelosi, Purwa Joshi, Ruth Leadbetter, Miriam Rodrigues, Stuart Mossman, Richard Roxburgh; J Neurol Neurosurg Psychiatry 2017;88:e1. doi:10.1136/jnnp-2017-316074.59

The ultrasound finding of enlarged peripheral nerves in FRDA patients points to a structural abnormality at peripheral nerve level. This contrasts with the reduced cross-sectional area seen in the cerebellar ataxia, neuronopathy, vestibular areflexia syndrome (CANVAS) which is thought to be due to a pure sensory ganglionopathy (Pelosi et al, Muscle Nerve 2017, in press). While the specific pathophysiology in FRDA is unknown, nerve enlargement suggests, in agreement with recent neuropathological studies, that axonal loss from dorsal root ganglionopathy is not the sole mechanism underlying sensory neuropathy of FRDA. Myelin and/or stromal abnormality at peripheral nerve level may play a significant role.

Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency

Abela L, Spiegel R, Crowther LM, Klein A, Steindl K, Papuc SM, Joset P, Zehavi Y, Rauch A, Plecko B, Simmons TL. PLoS ONE 12(5): e0176363. Doi:10.1371/journal.pone.0176363

Neurotoxicity induced by mitochondrial oxidative stress has been demonstrated for several neurodegenerative disorders. Furthermore, reduced aconitase activity has been found in Huntington disease, progressive supranuclear palsy, Friedreich ataxia and Alzheimer’s disease.
We demonstrate that metabolome profiling is a powerful tool to characterize disease mechanisms and pathogenicity of mutations.

Normalization of timed neuropsychological tests with the PATA rate and nine-hole pegboard tests

Saccà, F., Costabile, T., Abate, F., Liguori, A., Paciello, F., Pane, C., De Rosa, A., Manganelli, F., De Michele, G. and Filla, A. Journal of Neuropsychology. doi: 10.1111/jnp.12125

We tested the method on 24 patients with Friedreich Ataxia (FRDA), as a model of motor and speech impairment. In healthy controls, phonation or hand movement is 13.5–61.7% of total test time. In FRDA patients, the effect of normalization improved all test results (range: 0.51–48.4%; p < .001). FRDA patients had worst scores in all tests when compared to controls, and the difference remained significant after correction except for the Attentional Matrices. At the individual level, the normalization method improved equivalent scores with fever patients showing impaired scores after correction.

Dysphagia in Friedreich Ataxia

Megan J. Keage, Martin B. Delatycki, Isabelle Gupta, Louise A. Corben, Adam P. Vogel; Dysphagia (2017). doi:10.1007/s00455-017-9804-4

Oropharyngeal dysphagia is commonly present in individuals with FRDA and worsens with disease duration and severity. Individuals with FRDA are at risk of aspiration at any stage of the disease and should be reviewed regularly. Instrumental analysis remains the only reliable method to detect aspiration in this population. Dysphagia significantly affects the quality of life of individuals with FRDA. No reliable predictors of penetration or aspiration were identified.

Glutathione as a Redox Biomarker in Mitochondrial Disease—Implications for Therapy

Gregory M. Enns and Tina M. Cowan; Journal of Clinical Medicine 2017, 6(5), 50; doi:10.3390/jcm6050050

“Do you feel any better?” is a commonly asked question by a physician caring for a patient who has an underlying mitochondrial disorder during a clinic visit, typically after an interval of time following the start of various co-factors, vitamins, or supplements that may have a beneficial effect on mitochondrial function. The lack of validated, widely available, and objective markers of mitochondrial function makes this state-of-the-art of mitochondrial medicine in the 21st century somewhat discouraging.

Dysfunction of the mitochondrial electron transport chain is associated with redox imbalance and abnormally low GSH levels in primary genetic mitochondrial disorders, as well as conditions associated with secondary mitochondrial impairment, such as organic acidemias, Friedreich ataxia, Alzheimer disease, Parkinson disease, amyotropic lateral sclerosis, and Rett syndrome.
Friedreich ataxia patients also have evidence of redox abnormalities and mitochondrial dysfunction. A study of 14 unrelated Friedreich ataxia patients measured total and free GSH concentrations in erythrocytes by HPLC. Patients had a significant reduction of free glutathione levels, although total glutathione levels were comparable to controls. Friedreich ataxia patients were also found to have a significant increase in glutathione bound to hemoglobin in erythrocytes. Glutathione homeostasis was, therefore, considered to be impaired in Friedreich ataxia, raising the possibility that free radicals play a role in disease pathophysiology.

The new top 10 most expensive drugs on the planet

Endpoints News. by John Carroll
April 28, 2017 07:38 AM

¨5. Actimmune $572,292¨

Company: Horizon
Category: Rare disease – orphan drug
(Interferon gamma 1-b)

Approved for severe, malignant osteopetrosis and chronic granulomatous disease, rare genetic diseases, Actimmune noted last last year that the drug failed a Phase III for Friedreich’s ataxia. Horizon obtained a separate orphan drug designation for the drug when it decided to mount the study.